1. Field of the Invention
The present invention relates to a boron compound-layered double hydroxide (LDH) nanohybrid, and more particularly, to a stable boron compound-LDH nanohybrid that can be effectively used in boron neutron capture therapy, a method of preparing the boron compound-LDH nanohybrid, and a pharmaceutical composition comprising the boron compound-LDH nanohybrid, which can be used in boron neutron capture therapy.
2. Description of the Related Art
Boron neutron capture therapy is a type of cancer therapy. In boron neutron capture therapy, a compound containing boron-10 having affinity to a tumor is injected into a patient. When a low energy thermal or epithermal neutron beam having 0.025 eV is irradiated to the cancer, boron-10 capturing neutrons disintegrates into helium and lithium, that is, a nuclear fission reaction occurs, and thus high energy (unit: MeV) alpha particles (4He2+) that are very affective to biomolecules are emitted. The alpha particles emitted as a result of the nuclear fission reaction can selectively remove cancer cells to treat cancer. FIG. 1 is a schematic view illustrating a principle of the boron neutron capture therapy described above. Boron neutron capture therapy is used primarily for malignant glioblastoma multiforme and malignant melanoma that is a skin cancer, and, currently, research into use of boron neutron capture therapy on other types of cancer is being carried out.
If boron with a certain concentration is selectively delivered to a tumor cell, as maintaining at low levels of cytotoxicity, only cancer cells can be removed when exposed to neutrons irradiated from outside the body. A boron atom is not radioactive before it captures neutrons and also, neutrons themselves are harmless to the body. Therefore, before a boron atom captures neutrons, various factors can be changed to increase a cancer treatment effect. In this regard, various academic and medical research is being actively performed.
A boron neutron capture therapeutic agent may have various characteristics according to the site of a tumor. For example, a boron neutron capture therapeutic agent having high concentrations of boron should be stable, be able to easily enter a tumor cell, and be harmless to the body, and have a selective targeting effect with respect to a specific cancer tissue. To obtain a boron neutron capture therapeutic agent satisfying the requirements described above, research for various boron compounds and carriers for the delivery thereof have been carried out.
Until now, many boron neutron capture therapeutic agents have been developed. For example, US 2005/0165426A1 entitled “Carboranylporphyrins and uses thereof” discloses a carrier prepared by combining a boron compound with tetraphenylporphyrin compounds, wherein the carrier can be used in boron neutron capture therapy and photodynamic therapy, US 2003/0165426A1 entitled “Use of novel metalloporphyrins as imageable tumor-targeting agents for radiation therapy” discloses halogenated porphyrins having a carborane cage, and U.S. Pat. No. 6,517,808 entitled “Methods for boron delivery to mammalian tissue” discloses a carrier prepared by encapsulating boron compounds in the bilayer of a liposome. In addition, according to US 2002/0160969A1, nucleosides and oligonucleotides are introduced to a boron compound in order to increase affinity with respect to a tumor cell; WO 98/09973 entitled “Boron-containing amino carboxylic acid compounds and uses thereof” discloses a stable boron-substituted aromatic hydrocarbon linked to an amino carboxylic acid; and WO 96/00090 entitled“Boron-containing hormone analogs and methods of their use in imaging or killing cells having hormone receptors” discloses a novel compound prepared by attaching a specific ligand to a boron compound in order to selectively accumulate the boron compound at the site of a cell related to a specific hormone. Furthermore, WO00/43401 entitled “Boron steroid mimics and pharmaceutical compounds” discloses boron heterocycle steroid mimics for treating cancer cells.
As described above, research into boron neutron capture therapeutic agents is ongoing. Specifically, ligands or nucleic acids, which are reactive to a specific cell, are attached to a boron compound to obtain selectivity with respect to a specific cancer cell. In addition, carriers for effectively delivering a large amount of boron to cancer cells are being developed. However, any inorganic drug carrier for delivering a boron compound has not yet been developed.
In addition, conventional methods described above are not effective for performing boron neutron capture therapy. Therefore, there is a need to develop a method of sufficiently improving the cell membrane permeability and selectivity of a boron compound with respect to cancer cells.
Meanwhile, a layered double hydroxide (LDH), also known as a hydrotalcite mimic compound, has a structure similar to hydrotalcite having a layered double hydroxide structure formed of zinc and aluminum, wherein zinc and aluminum are substituted with other divalent or trivalent metal. LDH has a positive charge due to the presence of trivalent metallic ions in between layers of LDH, and thus various anions can be introduced between the layers. However, LDH has not been used as a drug carrier of a boron compound that is used in a specific radioactive cancer therapy, such as boron neutron capture therapy.